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The TLR4 antagonist CRX-526 protects against advanced diabetic nephropathy
Miao Lin1, Wai Han Yiu, Rui Xi Li
1Division of Nephrology, Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong.
Abstract:
We recently showed that Toll-like receptor (TLR) TLR4 was overexpressed in the human diabetic kidney, which could promote tubular inflammation. Here we explored whether the TLR4 antagonist, CRX-526, has therapeutic potential to attenuate renal injuries and slow the progression of advanced diabetic nephropathy in wild-type and endothelial nitric oxide synthase (eNOS) knockout mice. In the latter, the endogenous TLR4 ligand, high-mobility group box 1, was upregulated more than in wild-type animals. Four weeks after streptozotocin induction of diabetes, mice were injected with either CRX-526 or vehicle for 8 weeks. CRX-526 significantly reduced albuminuria and blood urea nitrogen without altering blood glucose and systolic blood pressure in diabetic mice. Glomerular hypertrophy, glomerulosclerosis, and tubulointerstitial injury were attenuated by CRX-526, which was associated with decreased chemokine (C-C motif) ligand (CCL)-2, osteopontin, CCL-5 overexpression, subsequent macrophage infiltration, and collagen deposition. These effects were associated with inhibition of TGF-β overexpression and NF-κB activation. In vitro, CRX-526 inhibited high glucose-induced osteopontin upregulation and NF-κB nuclear translocation in cultured human proximal tubular epithelial cells. Thus, we provided evidence that inhibition of TLR4 with the synthetic antagonist CRX-526 conferred renoprotective effects in eNOS knockout diabetic mice with advanced diabetic nephropathy.
Insights
The Toll-like receptor 4 (TLR4) antagonist CRX-526 shows therapeutic potential for diabetic nephropathy. It attenuated kidney injury and inflammation in diabetic mice, suggesting a renoprotective effect.
Area of Science:
- Nephrology
- Immunology
- Pharmacology
Background:
- Toll-like receptor 4 (TLR4) is overexpressed in diabetic kidneys, promoting inflammation.
- Endothelial nitric oxide synthase (eNOS) knockout mice exhibit higher levels of the TLR4 ligand, high-mobility group box 1, during diabetes.
Purpose of the Study:
- To investigate the therapeutic potential of the TLR4 antagonist CRX-526 in attenuating renal injuries and slowing diabetic nephropathy progression.
- To evaluate CRX-526 efficacy in both wild-type and eNOS knockout diabetic mouse models.
Main Methods:
- Diabetes was induced using streptozotocin in wild-type and eNOS knockout mice.
- Mice were treated with CRX-526 or vehicle for 8 weeks.
- Renal function, histological changes, inflammatory markers, and signaling pathways (TGF-β, NF-κB) were assessed. In vitro studies used cultured human proximal tubular epithelial cells.
Main Results:
- CRX-526 significantly reduced albuminuria and blood urea nitrogen in diabetic mice, without affecting blood glucose or blood pressure.
- Histological analysis revealed attenuated glomerular hypertrophy, glomerulosclerosis, and tubulointerstitial injury.
- CRX-526 decreased overexpression of CCL-2, osteopontin, and CCL-5, reducing macrophage infiltration and collagen deposition. It also inhibited TGF-β and NF-κB activation.
- In vitro, CRX-526 inhibited high glucose-induced osteopontin upregulation and NF-κB nuclear translocation.
Conclusions:
- CRX-526 demonstrates significant renoprotective effects in advanced diabetic nephropathy, particularly in eNOS knockout mice.
- Inhibition of TLR4 signaling via CRX-526 offers a promising therapeutic strategy for diabetic kidney disease.
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